Anatomical abnormalities of the anterior cingulate and paracingulate cortex in patients with bipolar I disorder

Abnormalities of the anterior cingulate cortex (ACC) are thought to be involved in the pathophysiology of bipolar disorder, but structural Magnetic Resonance Imaging (MRI) studies have reported variable findings. Reasons for this include a failure to consider variability in regional cortical folding patterns and a reliance on relatively coarse measures (e.g., volume) to index anatomical change. We sought to overcome these limitations by combining a novel protocol for parcellating the ACC and adjacent paracingulate cortex (PaC) that accounts for inter-individual variations in sulcal and gyral morphology with a cortical surface-based approach that allowed calculation of regional grey matter volume, surface area and cortical thickness in 24 patients with bipolar I disorder and 24 matched controls. No changes in grey matter volume or surface area were identified in any region, but patients did show significant reductions in cortical thickness in the left rostral PaC and right dorsal PaC that were not attributable to group differences in cortical folding patterns. These findings suggest that bipolar disorder is associated with more pronounced changes in the PaC, and that reliance on volumetric measures alone may obscure more subtle differences.     

De novo malignancies after renal transplantation--a single-center experience in the Balkans

The occurrence of malignancies is a well-known serious complication after organ transplantation. Despite the fact that many factors may be involved, the pathogenesis is still unclear. The aim of the present study was to examine the incidence and clinical characteristics of de novo malignancies that arise after renal transplantation over a 13-year experience in a single center in the Balkan Peninsula. During this period, 185 renal transplantations (139 living related and 46 cadaveric) were followed in our department. Overall, 19 malignancies (9.78%) were observed in 15 patients (7.8%). The mean age of these patients was 45 years (range, 21-53 years). Ten patients (55%) developed skin cancers: 8 squamous and 2 basal cell. Kaposi's sarcomas were found in 3 patients (16.6%, 1 visceral form). We also detected 1 breast cancer, 1 seminoma, 1 colon cancer, 1 urogenital-transitional cell-like cancer, 1 renal cell carcinoma, 1 plasmacytoma, and 1 retroperitoneal sarcoma after an ABO incompatible transplantation. All cancers were de novo malignancies that presented at a mean time of 21 months (range, 2-52 months) after surgery. In conclusion, the incidence of malignancy in the present series was similar to that reported elsewhere. The predominance of skin cancers was understandable bearing in mind the sunshine. The appearance of skin malignancies in our group of patients was earlier, more severe, and multiple sites. No cases of posttransplantation lymphoproliferative disorders were observed. Careful clinical examination and long-term screening protocols are needed for early detection and treatment of this life-threatening complication among the transplant population.     

Non‐Clinical Factors Associated With Referrals to Periodontal Specialists: A Systematic Review

Background: Comprehensive understanding of the referral process and factors associated with it will assist general dentist (GD)–periodontist relationships and benefit patient care and services. Non‐clinical factors (NCFs) influence clinical decision making but are rarely considered. The objective of this review is to identify NCFs found to be associated with referrals to periodontal specialists. Methods: A systematic review of English‐language literature was conducted according to Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. An electronic search was carried out using the Cumulative Index to Nursing and Allied Health Literature, Dentistry and Oral Sciences Sources, and PubMed. Search terms used included: 1) refer; 2) referral; 3) periodontal; and 4) periodontist. Potentially relevant publications were analyzed in detail using predetermined inclusion and exclusion criteria. Selected papers were assessed using the Mixed Methods Appraisal Tool, and data extracted were thematically synthesized. Results: Ten studies that examined NCFs fulfilled inclusion criteria. Four NCF themes identified were practice‐, GD‐, patient‐, and periodontist‐related factors. Conclusions: Limited literature is available on NCFs associated with referrals to periodontal specialists. Within the limits of this systematic review, NCFs affecting the referral process are practice‐, GD‐, patient‐, and periodontist‐related factors. These vary among different GD populations studied. Factors that could be targeted to improve referral processes include geographic location, undergraduate training, and continuing professional development.     

Temperate and lytic bacteriophages programmed to sensitize and kill antibiotic-resistant bacteria

The increasing threat of pathogen resistance to antibiotics requires the development of novel antimicrobial strategies. Here we present a proof of concept for a genetic strategy that aims to sensitize bacteria to antibiotics and selectively kill antibiotic-resistant bacteria. We use temperate phages to deliver a functional clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated (Cas) system into the genome of antibiotic-resistant bacteria. The delivered CRISPR-Cas system destroys both antibiotic resistance-conferring plasmids and genetically modified lytic phages. This linkage between antibiotic sensitization and protection from lytic phages is a key feature of the strategy. It allows programming of lytic phages to kill only antibiotic-resistant bacteria while protecting antibiotic-sensitized bacteria. Phages designed according to this strategy may be used on hospital surfaces and hand sanitizers to facilitate replacement of antibiotic-resistant pathogens with sensitive ones.The clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) proteins have evolved in prokaryotes to protect against phage attack and undesired plasmid replication by targeting foreign DNA or RNA (1–3). These systems target nucleic acids, based on short DNA sequences, called spacers, that exist between repeats in the CRISPR array. Transcribed spacers guide Cas proteins to homologous sequences within the foreign nucleic acid, called protospacers, which are subsequently cleaved. The CRISPR-Cas systems have revolutionized molecular biology by providing efficient tools to precisely engineer genomes and manipulate gene expression in various organisms (4–10). CRISPR-Cas systems have also recently been used to phenotypically correct genetic diseases in live animals (11), and their utility is being explored for various therapeutic approaches in mammals. Nevertheless, only limited studies have shown the use of CRISPR-Cas systems to target antibiotic resistance genes or a specific population of virulent bacterial strains (12–17).Two recent elegant studies demonstrated that phage-transferable CRISPR-Cas systems are capable of specifically killing pathogens or resensitizing them to antibiotics (16, 17). These studies, and another study (13), also showed that the transferred CRISPR-Cas system is capable of eliminating specific bacterial populations. Furthermore, they demonstrated that the system might be used against pathogens to effectively treat infected animals. Consequently, it was suggested that the system could be used as a potent antimicrobial agent. Nevertheless, although the results of these studies highlight the potential of a phage-transferable CRISPR-Cas system, the concept of using the system as a direct antimicrobial is similar to conventional phage therapy, which currently faces various obstacles (18). One major obstacle is phage administration into infected tissues; this stems from the phages’ immunogenicity and relative large size compared with antibiotics. One may argue that it would be more efficient to directly kill a pathogen by a lytic phage if it were possible to deliver the CRISPR-Cas–encoding cassette into this pathogen by a phage. Moreover, using the proposed systems in infected patients to resensitize pathogens to antibiotics while antibiotics counterselect for these sensitized pathogens would most likely fail due to escape mutants that are selected by the antibiotics.Here we demonstrate a strategy to counteract the emerging threat of antibiotic-resistant bacteria that evades the above shortcomings. Instead of directly killing the pathogens, we propose to sensitize the pathogens on surfaces or in the human skin flora while concomitantly enriching for these sensitized populations. Patients infected by these antibiotic-sensitive bacteria would thus be treatable by traditional antibiotics. In this strategy, the CRISPR-Cas system is used to destroy specific DNAs that confer antibiotic resistance and to concurrently confer a selective advantage to antibiotic-sensitive bacteria by virtue of resistance to lytic phages. The selective advantage enables to efficiently displace populations of nonsensitized bacteria by killing them with lytic phages. In contrast to conventional phage therapy, this approach does not require administration of phages into the host’s tissues. In addition, it does not aim to directly kill treated bacteria but rather to sensitize them to antibiotics and to kill the nonsensitized bacteria. Therefore, there is no counterselection against the sensitization. The strategy relies on CRISPR spacers that can be rationally designed to target any DNA sequence, including those that encode resistance genes and lytic phages. It thus allows genetically linking a trait that is beneficial to the bacteria (i.e., spacers protecting from lytic phage) with a trait that reverses drug resistance (i.e., spacers targeting resistance genes). The genetic linkage enables selecting antibiotic-sensitized bacterial population by using lytic phages. The integrated construct is designed not only to actively eradicate existing resistance genes but also to eliminate horizontal transfer of these genes between bacteria. Extended use of this technology should thus reduce drug-resistant populations of pathogens on major sources of contamination. Consequently, well-established antibiotics for which resistance currently exists could once again be effective.     

Reasons complicating the diagnosis and determination of the tubercular activity of respiratory organs]

The analysis of 260 cases of doubtful diagnosis and the definition of tuberculosis activity in newly-discovered patients demonstrated that these difficulties frequently resulted from nonadherence to conventional organizational, remedial and diagnostic measures in addition to the absence of continuity in the work of personnel of different medical institutions.     

Diagnosis and treatment of pleural lesions in sarcoidosis of the respiratory organs]

Among the 2775 respiratory sarcoidosis patients who were examined over the last ten years 278 (10%) had pleural affections: thickening of interlobular pleura and pleural deposits (98.2%), exudative pleurisy (1.1%) and spontaneous pneumothorax (0.7%). The most common pleural affection was found in sarcoidosis of stages II and III (16.8 and 70.8%, respectively). The clinical manifestations in all forms of this pathology had poor symptoms. Complex therapy proved to be highly effective. It included use of corticosteroids, antioxidants and immunomodulators; massive exudative pleurisy was managed by pleural puncture and removal of exudate.